"This was the first study to identify any mutation associated with sporadic early-onset PD . Subsequent studies in several countries identified additional novel ATP13A2 mutations in patients with early-onset disease (Table 1), including studies on individuals from Japan [12, 13], China [14–17], Europe , Iran [18, 19], Pakistan , Afghanistan , Lithuania , Inuit communities in Greenland , and Italy . "
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genes Parkin, Pink1, DJ-1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about the ATP13A2 gene, clinical characteristics of patients with PD-associated ATP13A2 mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting α-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss another ATP13A2 mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway whereby ATP13A2 mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets.
BioMed Research International 08/2014; 2014:371256. DOI:10.1155/2014/371256 · 3.17 Impact Factor
"Whereas wild-type ATP13A2 is localized to late endosomal and lysosomal membranes (Ramirez et al., 2006), the truncating KRS mutations lead to retention of the protein in the ER resulting in ER stress and proteasomal degradation via the ERassociated degradation pathway (Ugolino et al., 2011). Other missense mutations in ATP13A2 have been identified that are associated with early-onset Parkinsonism (Di Fonzo et al., 2007; Lin et al., 2008; Ning et al., 2008; Santoro et al., 2011). Similar to KRS mutations, homozygous missense mutations disrupt normal localization and function of ATP13A2 while heterozygous missense mutations may impair ATPase activity (Podhajska et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na(+)/K(+)-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2's putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events.
"These data indicated that ATP13A2 is a resident protein of the lysosomal membrane. Thus far, eight disease-associated mutations have been identified in the ATP13A2 gene, including one that we described initially      . To determine whether the mutant proteins were mislocalized and whether any such mislocalization has etiological importance , we assessed the subcellular localization of five pathogenic protein variants (Fig. 2A). "
[Show abstract][Hide abstract] ABSTRACT: Kufor-Rakeb syndrome (KRS) was originally described as an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia. ATP13A2 was identified as the causative gene in KRS. ATP13A2 encodes the ATP13A2 protein, which is a lysosomal type5 P-type ATPase, and ATP13A2 mutations are linked to autosomal recessive familial parkinsonism. Here, we report that normal ATP13A2 localizes in the lysosome, whereas disease-associated variants remain in the endoplasmic reticulum. Cathepsin D activity was decreased in ATP13A2-knockdown cells that displayed lysosome-like bodies characterized by fingerprint-like structures. Furthermore, an atp13a2 mutation in medaka fish resulted in dopaminergic neuronal death, decreased cathepsin D activity, and fingerprint-like structures in the brain. Based on these results, lysosome abnormality is very likely to be the primary cause of KRS/PARK9.
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